Urocortin-2

Also known as: Stresscopin-related peptide, Urocortin II, Urocortin-related peptide, UCN2, Q96RP3

Urocortin-2 (UCN2), also known as stresscopin-related peptide, is a 38-amino acid endogenous peptide belonging to the corticotropin-releasing factor (CRF) peptide family. Its mechanism of action is mediated through selective, high-affinity binding to the CRF receptor type 2 (CRF-R2), with negligible affinity for CRF-R1. Upon activation, CRF-R2 couples primarily to Gαs proteins, stimulating adenylyl cyclase and increasing intracellular cyclic AMP (cAMP) levels. This signaling cascade modulates stress adaptation by regulating cardiovascular function, energy metabolism, and behavioral responses. Unlike CRF, UCN2 does not significantly activate the hypothalamic-pituitary-adrenal (HPA) axis, instead exerting peripheral effects such as vasodilation, positive inotropy, and suppression of appetite. Key research findings from experimental studies demonstrate that UCN2 administration reduces mean arterial pressure and increases heart rate and cardiac output in rodent and primate models, suggesting a role in hemodynamic stress responses. In metabolic studies, UCN2 suppresses food intake and enhances insulin sensitivity, while chronic overexpression in transgenic mice leads to improved glucose tolerance and resistance to diet-induced obesity. Additionally, UCN2 has been shown to reduce anxiety-like behaviors in stress paradigms, likely via central CRF-R2 activation in limbic regions. However, its effects are context-dependent, with some studies reporting anxiogenic outcomes under specific conditions. Clinically, UCN2 is considered an experimental therapeutic candidate for conditions involving dysregulated stress responses, such as heart failure, metabolic syndrome, and anxiety disorders. Its selective CRF-R2 agonism offers a potential advantage over non-selective CRF receptor ligands by minimizing HPA axis overactivation. Despite promising preclinical data, no human clinical trials have been completed, and safety, pharmacokinetics, and efficacy remain unestablished. For research purposes only — not medical advice.

Key data

Mechanism of action

Hormone that plays a central role in whole body adaptation to stress (PubMed:11329063). Released by the hypothalamus primarily in response to physical or psychological stress and acts by binding to CRH receptor CRHR2 (PubMed:20966082). UCN2-dependent signaling regulates cardiovascular function, promotes skeletal muscle hypertrophy and manage energy balance and acts as an anorexigenic agent (By similarity). In contrast to CRH and UCN, does not activate the hypothalamus-pituitary-adrenal axis to promote corticotropin hormone (ACTH) production (PubMed:11329063)

Research & studies

Frequently asked questions

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